Effects of the direct thrombin inhibitor dabigatran and its orally active prodrug, dabigatran etexilate, on thrombus formation and bleeding time in rats

Thrombosis and Haemostasis

Volumn 98, Issue 2, 2007, Pages 333-338

  Wienen, Wolfgang ^a   Stassen, Jean Marie ^b   Priepke, Henning ^a   Ries, Uwe Joerg ^a   Hauel, Norbert ^a  

^a BOEHRINGER INGELHEIM PHARMA GMBH AND CO KG   (Germany)

^b Thromb X NV   (Belgium)

Author keywords

Activated partial thromboplastin time; Anticoagulant; Dabigatran etexilate; Direct thrombin inhibitor; Thrombosis

Indexed keywords

DABIGATRAN; DABIGATRAN ETEXILATE; HEPARIN; LEPIRUDIN; MELAGATRAN; PRODRUG; THROMBIN INHIBITOR;

ANIMAL EXPERIMENT; ANIMAL MODEL; ANTICOAGULATION; ARTICLE; BLEEDING TENDENCY; BLEEDING TIME; BOLUS INJECTION; CONTROLLED STUDY; DRUG ACTIVITY; MALE; NONHUMAN; PRIORITY JOURNAL; RAT; SINGLE DRUG DOSE; STATISTICAL SIGNIFICANCE; TAIL; THROMBOEMBOLISM; THROMBOGENESIS; VEIN THROMBOSIS;

ANIMALS; ANTICOAGULANTS; BENZIMIDAZOLES; BLEEDING TIME; DOSE-RESPONSE RELATIONSHIP, DRUG; DRUG ADMINISTRATION ROUTES; DRUG EVALUATION, PRECLINICAL; PRODRUGS; PYRIDINES; RATS; THROMBOSIS;

EID: 34547924093     PISSN: 03406245     EISSN: None     Source Type: Journal    
DOI: 10.1160/TH07-02-0113     Document Type: Article

References (31)

1. Becattini C, Agnelli G, Emmerich J, et al. Initial treatment of venous thromboembolism. Thromb Haemost 2006; 96: 242-250.
2. Hirsh J, Warkentin TE, Shaughnessy SG, et al. Heparin and low-molecular-weight heparin: mechanisms of action, pharmacokinetics, dosing, monitoring, efficacy, and safety. Chest 2001; 119 (1 Suppl): 64S-94S.
3. Hirsh J, Dalen J, Anderson DR, et al. Oral anticoagulants: mechanism of action, clinical effectiveness, and optimal therapeutic range. Chest 2001; 119 (1 Suppl): 8S-21S.
4. Weitz JI. Emerging anticoagulants for the treatment of venous thromboembolism. Thromb Haemost 2006; 96: 274-284.
5. Lind SE. The hemostatic system. In: Blood: Principles and practice of hematology. Philadelphia, Lippincott 1995: 949-973.
6. Di Nisio M, Middeldorp S, Büller HR. Direct thrombin inhibitors. N Engl J Med 2005; 353: 1028-1040.
7. Weitz JI, Hudoba M, Massel D, et al. Clot-bound thrombin is protected from inhibition by heparin-antithrombin III but is susceptible to inactivation by anti-thrombin III-independent inhibitors. J Clin Invest 1990; 86: 385-391.
8. Weitz JI, Leslie B, Hudoba M. Thrombin binds to soluble fibrin degradation products where it is protected from inhibition by heparin-antithrombin but susceptible to inactivation by antithrombin-independent inhibitors. Circulation 1998; 97: 544-552.
9. Gustafsson D, Nystrom J, Carlsson S, et al. The direct thrombin inhibitor melagatran and its oral prodrug H376/95: intestinal absortion properties, biochemical and pharmacodynamic effects. Thromb Res 2001; 101: 171-181.
10. Gustafsson D, Bylund R, Antonsson T, et al. A new oral anticoagulant: the 50-year challenge. Nature Rev Drug Discovery 2004; 3: 649-659.
11. Boos CJ, Lip GYH. Ximelagatran: An eulogy. Thromb Res 2006; 118: 301-304.
12. Hauel NH, Nar H, Priepke H, et al. Structure-based design of novel potent nonpeptide thrombin inhibitors. J Med Chem 2002 45: 1757-1766.
13. Ries UJ, Wienen W. Serine proteases as targets for antithrombotic therapy. Drugs Future 2003; 28: 355-370.
14. Herbert JM, Bernat A, Maffrand JP, Importance of platelets in experimental venous thrombosis in the rat. Blood 1992; 80: 2281-2286.
15. Gustafsson D, Elg M, Lenfors S, et al. Effects of inogatran, a new low-molecular-weight thrombin inhibitor, in rat models of venous and arterial thrombosis, thrombolysis and bleeding time. Blood Coagul Fibrinolysis 1996; 7: 69-79.
16. Leadley RJ Jr, Chi L, Rebello SS, et al. Contribution of in vivo models of thrombosis to the discovery and development of novel antithrombotic agents. J Pharmacol Toxicol Methods 2000; 43: 101-116.
17. Eriksson BI, Carlsson S, Halvarsson M, et al. Antithrombotic effect of two low molecular weight thrombin inhibitors and a low-molecular weight heparin in a caval vein thrombosis model in the rat. Thromb Haemost 1997; 78: 1404-1407.
18. Peternel L, Stegnan M, Drevensek G, et al. Antithrombotic potential of new direct thrombin inhibitors built on the azaphenylalanine scaffold in two rat venous thrombosis models. Thromb Haemost 2005; 93: 437-442.
19. Just M, Tripier D, Seiffge a Antithrombotic effects of recombinant hirudin in different animal models. Haemostasis 1991; 21 (Suppl 1): 80-87.
20. Elg M, Gustafsson D, Carlsson S. Antithrombotic effects and bleeding time of thrombin inhibitors and warfarin in the rat. Thromb Res 1999; 94: 187-197.
21. Elg M, Gustafsson D, Deinum J. The importance of enzyme inhibition kinetics for the effect of thrombin inhibitors in a rat model of arterial thrombosis. Thromb Haemost 1997; 78: 1286-1292.
22. Eikelboom JW, Hirsh J. Monitoring unfractionated heparin with the aPTT: Time for a fresh look. Thromb Haemost 2006; 96: 547-552.
23. Walenga, JM, Hoppensteadt DA. Monitoring the new antithrombotic drugs. Sem Thromb Hemost 2004; 30: 683-695.
24. Carlsson SC, Mattsson C, Eriksson UG, et al. A review of the effects of the oral direct thrombin inhibitor ximelagatran on coagulation assays. Thromb Res 2005; 115: 9-18.
25. Berry CN, Lassalle G, Lunven C, et al. SSR182289A, a novel, orally active thrombin inhibitor: In vitro profile and ex vivo anticoagulant activity. J Pharmacol Exp Ther 2002; 303: 1189-1198.
26. Eriksson BI, Dahl OE, Ahnfelt L, et al. Dose escalating safety study of a new oral direct thrombin inhibitor, dabigatran etexilate, in patients undergoing total hip replacement: BISTRO I. J Thromb Haemost 2004; 2: 1573-1580.
27. Eriksson BI, Dahl OE, Büller HR, et al. for the BISTRO II Study Group. A new oral direct thrombin inhibitor, dabigatran etexilate, compared with enoxaparin for prevention of thromboembolic events following total hip or knee replacement: the BISTRO II randomized trial. J Thromb Haemost 2005; 3: 103-111.
28. Lorrain J, Millet L, Lechaire I, et al. Antithrombotic properties of SSR182289A, a new, orally active thrombin inhibitor. J Pharmacol Exp Ther 2003; 304: 567-574.
29. Sato K, Kawasaki T, Taniuchi Y, et al. YM-60828, a novel factor Xa inhibitor: Separation of its antithrombotic effects from its prolongation of bleeding time. Eur J Pharmacol 1997; 339: 141-146.
30. Perzborn E, Strassburger J, Wilmen A, et al. In vitro and in vivo studies of the novel antithrombotic agent BAY 59-7939 - an oral, direct factor Xa inhibitor. J Thromb Haemost 2005; 3: 514-521.
31. Rodgers RP, Levin J. A critical reappraisal of the bleeding time. Sem Thromb Hemost 1990; 16: 1-20.